Structural and functional characteristics of homing endonucleases.
Mobile genetic elements constitute a remarkably diverse group of nonessential selfish genes that provide no apparent function to the host. These selfish genes have been implicated in host extinction, speciation and architecture of genetic systems. Homing endonucleases, encoded by the open reading frames embedded in introns or inteins of mobile genetic elements, possess double-stranded DNA-specific endonuclease activity. They inflict sequence-specific double-strand breaks at or near the homing site in intron- or intein-less allele. Subsequently, through nonreciprocal exchange the insertion sequence (intron or intein) is transferred from an intein- or intron-containing allele to an intein- or intron-less allele. The components of host double-strand break repair pathway are thought to finish the "homing" process. Several lines of evidence suggest that homing endonucleases are capable of promoting transposition into ectopic sites within or across genomes for their survival as well as dispersal in natural populations. The occurrence of inteins at high frequencies serves as instructive models for understanding the mechanistic aspects of the process of homing and its evolution. This review focuses on genetic, biochemical, structural, and phylogenetic aspects of homing endonucleases, and their comparison with restriction endonucleases.


Molecular and pathological basis of HPV-negative cervical adenocarcinoma seen in a global study.
International surveys find HPV-negativity in up to 30% of cervical adenocarcinomas. We investigated the pathological diagnosis by expert consensus with immunohistochemistry and the presence of somatic mutations in recognised tumour genes in HPV-positive and negative cervical adenocarcinomas (CADC). A sample was selected of 45 paraffin-embedded cervical blocks diagnosed locally as usual cervical adenocarcinoma from a global study. These represented different diagnoses made at previous diagnostic review and HPV status. All were suitable for analysis for somatic tumour associated gene mutations. Three pathologists examined H/E slides and immunohistochemistry for p16, progesterone receptor and p53 and classified the cases. L1 genes from high-risk HPVs and low-risk HPVs were analysed by SPF10 PCR-DEIA-LiPA25 version 1 in whole tissue sections and microdissected tumour and retested by PCR for E6/E7 genes of hrHPVs if negative. Cases were analysed for microsatellite instability and next-generation sequencing mutation analysis. From the 45 cases, 20 cases of usual CADC were confirmed of which 17 (85%) were HPV-positive in tumour cells. The other 25 cases were reclassified as endometrial, serous, clear-cell and gastric-type adenocarcinomas and all were HPV-negative in tumour cells. Careful retesting for HPV DNA and IHC leads to more accurate identification of HPV-positive usual cervical adenocarcinomas. Endometrioid endometrial adenocarcinomas, other uterine adenocarcinoma with multiple somatic mutations were important in misclassification of HPV-negative cases locally managed as cervical adenocarcinoma, as was gastric-type adenocarcinoma with germline STK11 mutation in East Asia. Few consensuses confirmed HPV-negative usual cervical adenocarcinomas showed somatic tumorigenic mutations also seen in some HPV-positive usual CADC.


Characterizing Far-infrared Laser Emissions and the Measurement of Their Frequencies.
The generation and subsequent measurement of far-infrared radiation has found numerous applications in high-resolution spectroscopy, radio astronomy, and Terahertz imaging. For about 45 years, the generation of coherent, far-infrared radiation has been accomplished using the optically pumped molecular laser. Once far-infrared laser radiation is detected, the frequencies of these laser emissions are measured using a three-laser heterodyne technique. With this technique, the unknown frequency from the optically pumped molecular laser is mixed with the difference frequency between two stabilized, infrared reference frequencies. These reference frequencies are generated by independent carbon dioxide lasers, each stabilized using the fluorescence signal from an external, low pressure reference cell. The resulting beat between the known and unknown laser frequencies is monitored by a metal-insulator-metal point contact diode detector whose output is observed on a spectrum analyzer. The beat frequency between these laser emissions is subsequently measured and combined with the known reference frequencies to extrapolate the unknown far-infrared laser frequency. The resulting one-sigma fractional uncertainty for laser frequencies measured with this technique is ± 5 parts in 10(7). Accurately determining the frequency of far-infrared laser emissions is critical as they are often used as a reference for other measurements, as in the high-resolution spectroscopic investigations of free radicals using laser magnetic resonance. As part of this investigation, difluoromethane, CH2F2, was used as the far-infrared laser medium. In all, eight far-infrared laser frequencies were measured for the first time with frequencies ranging from 0.359 to 1.273 THz. Three of these laser emissions were discovered during this investigation and are reported with their optimal operating pressure, polarization with respect to the CO2 pump laser, and strength.


Oxidative stress in the aging substantia nigra and the etiology of Parkinson's disease.
Parkinson's disease prevalence is rapidly increasing in an aging global population. With this increase comes exponentially rising social and economic costs, emphasizing the immediate need for effective disease-modifying treatments. Motor dysfunction results from the loss of dopaminergic neurons in the substantia nigra pars compacta and depletion of dopamine in the nigrostriatal pathway. While a specific biochemical mechanism remains elusive, oxidative stress plays an undeniable role in a complex and progressive neurodegenerative cascade. This review will explore the molecular factors that contribute to the high steady-state of oxidative stress in the healthy substantia nigra during aging, and how this chemical environment renders neurons susceptible to oxidative damage in Parkinson's disease. Contributing factors to oxidative stress during aging and as a pathogenic mechanism for Parkinson's disease will be discussed within the context of how and why therapeutic approaches targeting cellular redox activity in this disorder have, to date, yielded little therapeutic benefit. We present a contemporary perspective on the central biochemical contribution of redox imbalance to Parkinson's disease etiology and argue that improving our ability to accurately measure oxidative stress, dopaminergic neurotransmission and cell death pathways in vivo is crucial for both the development of new therapies and the identification of novel disease biomarkers.


Mental health symptoms and patient-reported diabetes symptom burden: implications for medication regimen changes.
To examine the relative contribution of glycaemic control (HbA1C) and depressive symptoms on diabetes-related symptom burden (hypoglycaemia and hyperglycaemia) in order to guide medication modification. Secondary analysis of medical records data and questionnaires collected from a racially/ethnically diverse sample of adult patients with type 2 diabetes (n = 710) from seven outpatient clinics affiliated with an academic medical centre over a 1-year period as part of the Reducing Racial Disparities in Diabetes: Coached Care (R2D2C2) study. Results from linear regression analysis revealed that patients with high levels of depressive symptoms had more diabetes-related symptom burden (both hypoglycaemia and hyperglycaemia) than patients with low levels of depressive symptoms (βs = 0.09-0.17, Ps < 0.02). Furthermore, results from two logistic regression analyses suggested that the odds of regimen intensification at 1-year follow-up was marginally associated with patient-reported symptoms of hypoglycaemia [adjusted odds ratio (aOR) = 1.24, 95% CI: 0.98-1.58; P = 0.08] and hyperglycaemia (aOR = 1.21, 95% CI: 1.00-1.46; P = 0.05), after controlling for patients' HbA1C, comorbidity, insulin use and demographics. These associations, however, were diminished for patients with high self-reported hypoglycaemia and high levels of depressive symptoms, but not low depressive symptoms (interaction terms for hypoglycaemia by depressive symptoms, aOR = 0.98, 95% CI: 0.97-0.99; P = 0.03). Mental health symptoms are associated with higher levels of patient-reported of diabetes-related symptoms, but the association between diabetes-related symptoms and subsequent regimen modifications is diminished in patients with greater depressive symptoms. Clinicians should focus attention on identifying and treating patients' mental health concerns in order to address the role of diabetes-related symptom burden in guiding physician medication prescribing behaviour.


[Decisions of the psychiatric court of appeal of basle-city in the year 2000--procedure on appeal against compulsory admission in a Swiss canton].
We present the legislation of the compulsory admission and treatment of mentally ill persons in the Swiss canton of Basle-City. We inquired retrospectively the requests of the clinic and the appointed time given by the psychiatric court of appeal in the year 2000. With 320 compulsory admissions there were 118 appeals. The patients with organic mental disorders are older and we exclude them for further examination because of the completely different psychosocial background. In the remaining 107 cases the schizophrenic disorders are clearly over-represented (75 % vs. 27 % of all admissions). Women are approx. 9 years older, are discharged three times more frequently at the negotiation and retained against their will for a shorter time than men. Men are more frequently isolated and compulsorily treated. The regression analysis can explain between 10 % and 16 % of the variance of the duration of the compulsory hospitalisation by the days of hospitalisation in the last two years and by sex.


Effect of phosphine dose on sorption in wheat.
In spite of the extensive use of phosphine fumigation around the world to control insects in stored grain, and the knowledge that grain sorbs phosphine, the effect of concentration on sorption has not been quantified. A laboratory study was undertaken, therefore, to investigate the effect of phosphine dose on sorption in wheat. Wheat was added to glass flasks to achieve filling ratios of 0.25-0.95, and the flasks were sealed and injected with phosphine at 0.1-1.5 mg L(-1) based on flask volume. Phosphine concentration was monitored for 8 days at 25 degrees C and 55% RH. When sorption occurred, phosphine concentration declined with time and was approximately first order, i.e. the data fitted an exponential decay equation. Percentage sorption per day was directly proportional to filling ratio, and was negatively correlated with dose for any given filling ratio. Based on the results, a tenfold increase in dose would result in a halving of the sorption constant and the percentage daily loss. Wheat was less sorptive if it was fumigated for a second time. The results have implications for the use of phosphine for control of insects in stored wheat. This study shows that dose is a factor that must be considered when trying to understand the impact of sorption on phosphine concentration, and that there appears to be a limit to the capacity of wheat to sorb phosphine.


Reduced amygdalar and hippocampal size in adults with generalized social phobia.
Structural and functional brain imaging studies suggest abnormalities of the amygdala and hippocampus in posttraumatic stress disorder and major depressive disorder. However, structural brain imaging studies in social phobia are lacking. In total, 24 patients with generalized social phobia (GSP) and 24 healthy controls underwent 3-dimensional structural magnetic resonance imaging of the amygdala and hippocampus and a clinical investigation. Compared with controls, GSP patients had significantly reduced amygdalar (13%) and hippocampal (8%) size. The reduction in the size of the amygdala was statistically significant for men but not women. Smaller right-sided hippocampal volumes of GSP patients were significantly related to stronger disorder severity. Our sample included only patients with the generalized subtype of social phobia. Because we excluded patients with comorbid depression, our sample may not be representative. We report for the first time volumetric results in patients with GSP. Future assessment of these patients will clarify whether these changes are reversed after successful treatment and whether they predict treatment response.


Vitamin D Deficiency and Effects of Vitamin D Supplementation on Disease Severity in Patients with Atopic Dermatitis: A Systematic Review and Meta-Analysis in Adults and Children.
Research has investigated 25-hydroxyvitamin D (25(OH)D) levels in the Atopic Dermatitis (AD) population, as well as changes in AD severity after vitamin D (VitD) supplementation. We performed an up-to-date systematic review and meta-analysis of these findings. Electronic searches of MEDLINE, EMBASE and COCHRANE up to February 2018 were performed. Observational studies comparing 25(OH)D between AD patients and controls, as well as trials documenting baseline serum 25(OH)D levels and clinical severity by either SCORAD/EASI scores, were included. Of the 1085 articles retrieved, sixteen were included. A meta-analysis of eleven studies of AD patients vs. healthy controls (HC) found a mean difference of -14 nmol/L (95% CI -25 to -2) for all studies and -16 nmol/L (95% CI -31 to -1) for the paediatric studies alone. A meta-analysis of three VitD supplementation trials found lower SCORAD by -11 points (95% CI -13 to -9, p < 0.00001). This surpasses the Minimal Clinical Important Difference for AD of 9.0 points (by 22%). There were greater improvements in trials lasting three months and the mean weighted dose of all trials was 1500-1600 IU/daily. Overall, the AD population, especially the paediatric subset, may be at high-risk for lower serum 25(OH)D. Supplementation with around 1600 IU/daily results in a clinically meaningful AD severity reduction.


Tracking mouse visual pathways with WGA transgene.
By use of wheat germ agglutinin (WGA) cDNA as a transgene, we have succeeded in generating a transgenic mouse line in which the visual pathways can be accurately and reproducibly visualized. The WGA transgene was expressed in the retinal rod bipolar cells under the control of mouse L7 promoter. The transgene product, WGA protein, was transferred from the bipolar cells to the amacrine cells and the ganglion cells across synapses in the retinal neural circuitry and further conveyed along the optic nerve to the visual centers such as the suprachiasmatic nucleus, the lateral geniculate nucleus, the pretectal nucleus and the superior colliculus. By crossing the WGA-expressing transgenic mice with the retinal degeneration mutant mice, we analyzed change in the visual pathways by monitoring WGA immunoreactivity and found that the disorganization process of the visual pathways was relatively slow in spite of the rapid degeneration of the photoreceptor cells. Thus, this transgenic mouse line would provide a useful tool for analyzing phenotypic changes in the visual pathways of various mutant mice.


[Topical Fk506 in inflammatory corneal and conjunctival diseases. A pilot study].
Topical corticosteroids are the only effective measure in serious inflammatory corneal and conjunctival diseases. Although results obtained with topical cyclosporin A are encuraging it is not effective in all patients. The mode of action of Fk506 is similar to that of cyclosporin A, i.e. it exerts an inhibitory effect on transcription of interleukin 2 in T lymphocytes. The immunosuppressive potential of Fk506, however, is much larger. Furthermore, it penetrates more easily into cornea and conjunctiva. To find out whether the theoretical advantages of topical Fk506 can be translated into clinical practice, a selected group of patients refractory to conventional therapy was treated in this pilot study. Fk506 0.06 % was administered initially three times daily in 15 patients with atopic blepharokeratoconjunctivitis, Mooren's ulcer, ocular pemphigoid, Thygeson's superficial punctate keratitis, nummular adenoviral keratitis, graft-versus-host reaction of the conjunctiva and steroid response glaucoma after penetrating keratoplasty. Within a follow-up of 26 +/- 15 weeks improvement was recorded in 5/15 patients and stabilization in 5/15 patients. In two patients progression of the disease was noted (one patient with progression of ocular pemphigoid, another patient with suspected automutilation). Premature withdrawal the drug was judged to be necessary in two patients with ocular surface disorders and in one patient with non-compliance. Topical Fk506 seems to be a promising new immunosuppressive drug for patients with atopic blepharokeratoconjunctivitis, Thygeson's superficial punctate keratitis and nummular adenoviral keratitis. Exact efficacy in these and other corneal and conjunctival inflammatory diseases has to be determined in randomised clinical studies. Before these studies may start the risk of side-effects must be reduced via an improvement of the drops.


The Spatial Extent of Pain Is Associated with Pain Intensity, Catastrophizing and Some Measures of Central Sensitization in People with Frozen Shoulder.
The aim of this cross-sectional study was to explore the spatial extent of pain and its association with clinical symptoms, psychological features, and pain sensitization in people with frozen shoulder (FS). Forty-eight individuals with FS completed pain drawings (PDs) and reported their clinical symptoms including pain intensity (Visual Analogue Scale) and shoulder disability (Shoulder Pain and Disability Index). Moreover, pain sensitization measurements (pressure pain thresholds, temporal summation, conditioned pain modulation, and Central Sensitization Inventory (CSI)) were assessed. Psychological features were assessed by Pain Catastrophizing Scale (PCS) and Pain Vigilance and Awareness Questionnaire. Pain frequency maps were generated, Margolis rating scale was used for pain location, and Spearman correlation coefficients were computed. The mean (SD) pain extent was 12.5% (6.7%) and the most common painful area was the anterolateral shoulder region (100%). Women presented a more widespread pain distribution compared with men. Significant positive associations were obtained between pain extent and current pain intensity (rs = 0.421, p < 0.01), PCS (rs = 0.307, p < 0.05) and CSI (rs = 0.358, p < 0.05). The anterolateral region of the shoulder was the most common painful area in people with FS. Women with FS presented more extended areas of pain; and a more widespread distribution of pain was correlated with higher levels of pain, pain catastrophizing and pain sensitization.


CYP26A1 gene promoter is a useful tool for reporting RAR-mediated retinoid activity.
Of numerous genes regulated by retinoic acid (RA), CYP26A1 is the most inducible gene by RA. In this study, we have used a shortened construct form, E4, of the CYP26A1 gene promoter, in a promoter-less vector with either luciferase or red fluorescent protein (RFP) as the reporter gene and have tested its responses to retinoids in transfected HepG2 and HEK293T cells. The promoter responded linearly to a wide concentration range of RA in cells cotransfected with retinoic acid receptors. It also responded quantitatively to retinol and other retinoids. An isolated clonal line of HEK293T cells permanently transfected with the promoter driving the expression of RFP responded to both RA and retinol, and the responses could be measured by fluorescence microscopy and flow cytometry. The promoter was used to assess the retinoid activity of 3 novel synthetic retinoid analogues, as well as of the intact serum samples of rats. Among the synthetic retinoid analogues tested, EC23 is more potent than RA at lower concentrations and was more stable than RA. The retinoid activities could be measured in control rat serum samples and were increased in the serum of RA-treated rats. This system offers a biologically-based alternative to mass-based retinoid analysis.


Intronic deletions in the SLC34A3 gene cause hereditary hypophosphatemic rickets with hypercalciuria.
Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare metabolic disorder, characterized by hypophosphatemia and rickets/osteomalacia with increased serum 1,25-dihydroxyvitamin D [1,25-(OH)(2)D] resulting in hypercalciuria. Our objective was to determine whether mutations in the SLC34A3 gene, which encodes sodium-phosphate cotransporter type IIc, are responsible for the occurrence of HHRH. Mutation analysis of exons and adjacent introns in the SLC34A3 gene was conducted at an academic research laboratory and medical center. Members of two unrelated families with HHRH participated in the study. Two affected siblings in one family were homozygous for a 101-bp deletion in intron 9. Haplotype analysis of the SLC34A3 locus in the family showed that the two deletions are on different haplotypes. An unrelated individual with HHRH was a compound heterozygote for an 85-bp deletion in intron 10 and a G-to-A substitution at the last nucleotide in exon 7. The intron 9 deletion (and likely the other two mutations) identified in this study causes aberrant RNA splicing. Sequence analysis of the deleted regions revealed the presence of direct repeats of homologous sequences. HHRH is caused by biallelic mutations in the SLC34A3 gene. Haplotype analysis suggests that the two intron 9 deletions arose independently. The identification of three independent deletions in introns 9 and 10 suggests that the SLC34A3 gene may be susceptible to unequal crossing over because of sequence misalignment during meiosis.


Random survival forests with multivariate longitudinal endogenous covariates.
Predicting the individual risk of clinical events using the complete patient history is a major challenge in personalized medicine. Analytical methods have to account for a possibly large number of time-dependent predictors, which are often characterized by irregular and error-prone measurements, and are truncated early by the event. In this work, we extended the competing-risk random survival forests to handle such endogenous longitudinal predictors when predicting event probabilities. The method, implemented in the R package DynForest, internally transforms the time-dependent predictors at each node of each tree into time-fixed features (using mixed models) that can then be used as splitting candidates. The final individual event probability is computed as the average of leaf-specific Aalen-Johansen estimators over the trees. Using simulations, we compared the performances of DynForest to accurately predict an event with (i) a joint modeling alternative when considering two longitudinal predictors only, and with (ii) a regression calibration method that ignores the informative truncation by the event when dealing with a large number of longitudinal predictors. Through an application in dementia research, we also illustrated how DynForest can be used to develop a dynamic prediction tool for dementia from multimodal repeated markers, and quantify the importance of each marker.


[Effect of IP3 on BK channels of porcine coronary artery smooth muscle cells].
D-myo-inositol 1,4,5-trisphosphate (IP(3)) plays an important role in signal transduction. It releases Ca(2+) from intracellular sites, which activates the Ca(2+)-dependent channels such as large-conductance Ca(2+)-activated potassium channels (BK channels). The present study was therefore designed to determine if the activity of BK channels in porcine coronary artery smooth muscle cells was increased by IP(3). Using the inside-out patch-clamp technique, the activity of single BK channels was recorded in porcine coronary artery smooth muscle cells. In excised inside-out membrane patches, IP(3) (10-50 micromol/L) enhanced the open probability (Po) of BK channels in a dose-dependent manner in the intracellular side of inside-out patches and its effect was almost completely abolished by washout. The open-state probability of the BK channels increased from a control level of 0.0402+/-0.0152 to 0.1365+/-0.0212 (20 micromol/L IP(3)) and 0.1865+/-0.0175 (30 micromol/L IP(3)). IP(3) decreased the mean close time markedly, but had no effect on the amplitude of BK channels. The activation of IP(3) on BK channels did not decline. The metabolite of IP(3) had no obvious effect on BK channels. This study provides evidence that IP(3) activates BK channels in porcine coronary artery smooth muscle cells in a dose-dependence manner.


MHC class I-deficient natural killer cells acquire a licensed phenotype after transfer into an MHC class I-sufficient environment.
In MHC class I-deficient hosts, natural killer (NK) cells are hyporesponsive to cross-linking of activation receptors. Functional competence requires engagement of a self-major histocompatability complex (MHC) class I-specific inhibitory receptor, a process referred to as "licensing." We previously suggested that licensing is developmentally determined in the bone marrow. In this study, we find that unlicensed mature MHC class I-deficient splenic NK cells show gain-of-function and acquire a licensed phenotype after adoptive transfer into wild-type (WT) hosts. Transferred NK cells produce WT levels of interferon-γ after engagement of multiple activation receptors, and degranulate at levels equivalent to WT NK cells upon coincubation with target cells. Only NK cells expressing an inhibitory Ly49 receptor specific for a cognate host MHC class I molecule show this gain-of-function. Therefore, these findings, which may be relevant to clinical bone marrow transplantation, suggest that neither exposure to MHC class I ligands during NK development in the BM nor endogenous MHC class I expression by NK cells themselves is absolutely required for licensing.


Tracking and promoting the usage of a COVID-19 contact tracing app.
Digital contact tracing apps have been introduced globally as an instrument to contain the COVID-19 pandemic. Yet, privacy by design impedes both the evaluation of these tools and the deployment of evidence-based interventions to stimulate uptake. We combine an online panel survey with mobile tracking data to measure the actual usage of Germany's official contact tracing app and reveal higher uptake rates among respondents with an increased risk of severe illness, but lower rates among those with a heightened risk of exposure to COVID-19. Using a randomized intervention, we show that informative and motivational video messages have very limited effect on uptake. However, findings from a second intervention suggest that even small monetary incentives can strongly increase uptake and help make digital contact tracing a more effective tool.


Management of tumor bed cysts after chemotherapeutic wafer implantation. Report of four cases.
Adjuvant use of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) wafers with surgical resection is becoming common for the treatment of malignant gliomas. Cyst formation in the tumor resection cavity is a recently described complication associated with the use of BCNU wafers. There is currently no report in which successful management of this complication without additional surgical intervention is described. The authors describe four patients in whom postoperative cysts developed in the tumor resection cavity after placement of BCNU wafers. These include a 38-year-old man with a left frontoparietal tumor, a 48-year-old man with a right frontal lobe tumor, a 78-year-old man with a left parietooccipital tumor, and a 61-year-old woman with a left frontotemporal tumor. Histopathological studies of biopsy samples revealed malignant glioma in each patient. All four patients had unremarkable perioperative courses, were discharged within 3 to 8 days of surgery, and subsequently returned with acute neurological deterioration. Follow-up magnetic resonance (MR) imaging demonstrated cyst formation with significant mass effect at the previous resection site. Three patients were treated with high-dose dexamethasone and returned to their neurological baseline over an 8-day period. The fourth patient improved after surgical drainage and biopsy sampling of the cyst, which revealed no evidence of infection or recurrent tumor, but again sought medical care 2 weeks later with cyst recurrence necessitating high-dose steroid therapy. On MR images at least a 30% reduction in cyst size was demonstrated in all four patients, each of whom remained clinically stable at 2, 6, 6, and 4 months of follow-up review. Neurosurgeons should be aware of the potential for postoperative cyst formation accompanied by clinically significant mass effect after BCNU wafer implantation, as well as the potential for successful nonsurgical management leading to clinical and radiological improvement.


Effect of immobilization stress on pipecolic acid transport in mouse brain areas and peripheral tissues.
Transport activity of d-pipecolic acid and of l-pipecolic acid in mouse brain and peripheral tissues were tested, and the effect of immobilization stress was described, along with the method for preparative, enantiomeric resolution and purification of d,l-pipecolic acid using high performance liquid chromatography equipped with a chiral column. It was found that l-isomer, an endogenous substance, was more rapidly transported to brain and liver than the d-isomer, non-endogenous one, which was more rapidly eliminated into the kidney. Immobilization stress caused acceleration of transport of l-pipecolic acid into the brain region, liver and heart, but not that of d-pipecolic acid. From these results it was suggested that the elevation of pipecolic acid concentration caused by stress might be exerted through its stimulatory effect on the transport of l-pipecolic acid into the tissues.


Soluble PD-L1 Expression in Circulation as a Predictive Marker for Recurrence and Prognosis in Gastric Cancer: Direct Comparison of the Clinical Burden Between Tissue and Serum PD-L1 Expression.
This study assessed programmed cell death ligand 1 (PD-L1) expression in primary tissues and soluble PD-L1 (sPD-L1) concentration in matched preoperative serum in gastric cancer (GC) patients to perform direct comparison between tissue and serum PD-L1 expression and to clarify the prognostic implication in GC. The study enrolled 180 GC patients who underwent surgery for GC at the authors' institution. The study evaluated tissue PD-L1 expression using immunohistochemistry and quantified sPD-L1 concentration in preoperative serum using enzyme-linked immunosorbent assay in GC patients. The findings showed that PD-L1 was overexpressed in GC tissues compared with normal mucosa. Tissue PD-L1 expression was significantly higher in the GC patients with advanced T stage, presence of lympho-vascular invasion, lymph node metastasis, and peritoneal metastasis. Furthermore, elevated tissue PD-L1 expression was significantly associated with poor prognosis for overall survival (OS) and disease-free survival (DFS). Serum sPD-L1 was significantly higher in the GC patients than in the healthy volunteers. Although serum sPD-L1 was not correlated with any clinicopathologic factors, the patients with high serum sPD-L1 showed poorer OS and DFS than those with low sPD-L1. Multivariate analyses showed that both elevated tissue PD-L1 and serum sPD-L1 were independent prognostic factors for poor OS [tissue PD-L1: hazard ratio (HR), 4.28; 95% confidence interval (CI), 1.43-12.8; P = 0.0094 vs. serum sPD-L1: HR, 11.2; 95% CI, 3.44-36.7; P = 0.0001] and poor DFS (tissue PD-L1: HR, 6.96; 95% CI, 2.48-19.6; P = 0.0002 vs. serum sPD-L1: HR, 8.7; 95% CI, 3.16-23.9; P < 0.0001) for the GC patients. Furthermore, infiltrative CD8- and Foxp3-positive T cells were significantly increased in the GC patients with elevated tissue PD-L1 expression. Both serum sPD-L1 and tissue PD-L1 expression may serve as predictive biomarkers for recurrence and prognosis in GC patients.


[A Case of Large Rectal Villous Adenoma Associated with Tenesmus and Body Weight Loss].
The patient was a 78-year-old man who was hospitalized with a 1-month history of tenesmus and body weight loss. Blood tests revealed a mild increase in tumor markers(CEA 9.7 ng/mL)and an elevation of the inflammatory response. Colonoscopic examination disclosed a full circular lateral spreading tumor(LST)extending from the second Houston valve to the rectosigmoidal region with a more than 10 cm length. Since invasion to the SM layer was suspected, endoscopic resection was judged inapplicable and laparoscopic low anterior resection with D2 lymph node dissection was performed, along with covering ileostomy. The final pathology diagnosis was villous adenoma with carcinoma in adenoma, showing multiple villous structures categorized as high dysplasia. Postoperatively, he was free from tenesmus and his body weight increased. In addition, normalization of the tumor markers occurred.


Animal experiments in radiotherapy I -- small animals.
This is a brief review of the contribution that the small laboratory animal, in particular the mouse, has made to experimental radiotherapy. Despite the great differences between mouse and man (e.g. size and life span), there are similarities of tissue cell kinetics and radiation response which greatly aid in the mouse-to-man extrapolation. The crucial advantage of being able to perform experiments with spontaneous tumors transplanted into syngeneic hosts is discussed. Examples are given of work using the tumor control dose (TCD50) endpoint, the endpoint dilution assay, two different clone-counting assays, and the tumor regrowth system. The sophistication that can be achieved with an animal as small as a mouse is illustrated by two studies: one of prolonged intra-arterial catheterization, the other of blood flow measurements in an irradiated limb.


Assessment of Obsessive Thoughts About COVID-19 in 7 Latin American Countries: Structure and Measurement Invariance of the Obsession With COVID-19 Scale.
The present study aimed to evaluate the measurement invariance of the Obsession with COVID-19 Scale (OCS) among seven Latin American countries: Bolivia, Brazil, Cuba, El Salvador, Guatemala, Paraguay, and Uruguay. Although the OCS has been used in several countries and languages, there is a need for approaches that better integrate the cross-cultural equivalence of the scale. A total of 3185 people participated in the study. The results indicated the presence of a unidimensional structure and good reliability indices for the OCS in each country. The alignment method indicated that the OCS is an invariant measure of COVID-19 obsession among the populations of seven Latin American countries. The findings based on IRT analysis indicated that all OCS items had adequate discrimination and difficulty parameters. The findings contribute to the understanding of the internal structure of the scale in different countries at the same time, something that has been pending evaluation.


Review of Renal Biopsies, A Single Center Experience.
No large study has been conducted on biopsy-proven nephropathies. Our aim was to report clinical and pathological pattern of kidney disease diagnosed by kidney biopsy in our center. This is a retrospective study on kidney biopsy during 7 years; we analyzed the results of kidney biopsies and their clinical data. Data were analyzed by SPSS 18.0 and a P < .05 was considered. In 1355 kidney biopsies (55.7% women, age = 33.2 ± 16.4), primary glomerulonephritis (GN) was the main feature (57.1%). The most common presentation was asymptomatic urine abnormality (32.3%). Lupus nephritis (24.5%), membranous GN (17.0%), and focal segmental glomerulosclerosis (13.9%) were the most frequent diagnosis. This study highlights the histopathological patterns of kidney disease in southern Iran. lupus nephritis, membranous GN, and focal segmental glomerulosclerosis are currently the three major diseases. These results have an important role in organizing renal health plans as an initial phase in our population.


Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial.
Multiple sclerosis is a degenerative inflammatory disease of the CNS characterised by immune-mediated destruction of myelin and progressive neuroaxonal loss. Myelin in the CNS is a specialised extension of the oligodendrocyte plasma membrane and clemastine fumarate can stimulate differentiation of oligodendrocyte precursor cells in vitro, in animal models, and in human cells. We aimed to analyse the efficacy and safety of clemastine fumarate as a treatment for patients with multiple sclerosis. We did this single-centre, 150-day, double-blind, randomised, placebo-controlled, crossover trial (ReBUILD) in patients with relapsing multiple sclerosis with chronic demyelinating optic neuropathy on stable immunomodulatory therapy. Patients who fulfilled international panel criteria for diagnosis with disease duration of less than 15 years were eligible. Patients were randomly assigned (1:1) via block randomisation using a random number generator to receive either clemastine fumarate (5·36 mg orally twice daily) for 90 days followed by placebo for 60 days (group 1), or placebo for 90 days followed by clemastine fumarate (5·36 mg orally twice daily) for 60 days (group 2). The primary outcome was shortening of P100 latency delay on full-field, pattern-reversal, visual-evoked potentials. We analysed by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT02040298. Between Jan 1, 2014, and April 11, 2015, we randomly assigned 50 patients to group 1 (n=25) or group 2 (n=25). All patients completed the study. The primary efficacy endpoint was met with clemastine fumarate treatment, which reduced the latency delay by 1·7 ms/eye (95% CI 0·5-2·9; p=0·0048) when analysing the trial as a crossover. Clemastine fumarate treatment was associated with fatigue, but no serious adverse events were reported. To our knowledge, this is the first randomised controlled trial to document efficacy of a remyelinating drug for the treatment of chronic demyelinating injury in multiple sclerosis. Our findings suggest that myelin repair can be achieved even following prolonged damage. University of California, San Francisco and the Rachleff Family.


Calciphylaxis with histologic changes of pseudoxanthoma elasticum.
Calciphylaxis is a rare condition of widespread calcification of tissues and blood vessels with accompanying vascular thrombosis and ischemic necrosis. Most cases develop in association with hyperparathyroidism in patients with chronic renal failure. Pseudoxanthoma elasticum (PXE) is a hereditary condition of abnormal elastic tissue structure that leads to widespread abnormalities of the skin, retina, and visceral organs. Histologic changes of PXE have been observed as coincidental findings in several conditions such as following trauma to the skin manifest as isolated plaques often in scars. We observed histologic findings of PXE in a patient with chronic renal failure who developed fatal calciphylaxis. Complete evaluation failed to reveal evidence of systemic findings of PXE. Histologic changes of PXE may be seen in patients with calciphylaxis as a coincidental finding. Rapidly developing soft tissue calcification may lead to the expression of the characteristic histopathologic findings of PXE without evidence of classic clinical manifestations of PXE. Calciphylaxis should be added to the list of disorders that may lead to microscopic PXE-like changes.


Colorectal cancer stem cells.
The cancer stem cell hypothesis predicts that only a subpopulation of cells within a tumor is responsible for driving growth. If this hypothesis were true, it would have a significant impact on our current treatment of cancer because conventional chemotherapy and radiotherapy target rapidly proliferating cells making up the bulk of the tumor, not specifically cancer stem cells. The aims of this review are to highlight the current evidence supporting the existence of cancer stem cells in colorectal cancer, to consider the relative merits of current cancer stem cell markers, and to discuss the implications of this on our current treatment of cancer. Published scientific articles were selected by searching the PubMed database by use of the terms "colorectal," "cancer," and "stem cells," and by use of the bibliographies of extracted articles. CD133, a glycosylated cell surface protein, has been demonstrated to isolate for a subpopulation of colorectal tumor cells enriched in cancer stem cells. However, only 1 in 262 CD133+ cells are able to initiate tumors. Other cancer stem cell markers have been investigated, but an overall need exists to identify more specific markers to allow further characterization of these cancer stem cells. We discuss how increased understanding of the distribution and behavior of cancer stem cells within tumors could have significant implications for the management of colorectal cancer, including screening, resection margins, sentinel node biopsy, determination of prognosis, and the development of novel therapeutic targets.


PinR mediates the generation of reversible population diversity in Streptococcus zooepidemicus.
Opportunistic pathogens must adapt to and survive in a wide range of complex ecosystems. Streptococcus zooepidemicus is an opportunistic pathogen of horses and many other animals, including humans. The assembly of different surface architecture phenotypes from one genotype is likely to be crucial to the successful exploitation of such an opportunistic lifestyle. Construction of a series of mutants revealed that a serine recombinase, PinR, inverts 114 bp of the promoter of SZO_08560, which is bordered by GTAGACTTTA and TAAAGTCTAC inverted repeats. Inversion acts as a switch, controlling the transcription of this sortase-processed protein, which may enhance the attachment of S. zooepidemicus to equine trachea. The genome of a recently sequenced strain of S. zooepidemicus, 2329 (Sz2329), was found to contain a disruptive internal inversion of 7 kb of the FimIV pilus locus, which is bordered by TAGAAA and TTTCTA inverted repeats. This strain lacks pinR and this inversion may have become irreversible following the loss of this recombinase. Active inversion of FimIV was detected in three strains of S. zooepidemicus, 1770 (Sz1770), B260863 (SzB260863) and H050840501 (SzH050840501), all of which encoded pinR. A deletion mutant of Sz1770 that lacked pinR was no longer capable of inverting its internal region of FimIV. The data highlight redundancy in the PinR sequence recognition motif around a short TAGA consensus and suggest that PinR can reversibly influence the wider surface architecture of S. zooepidemicus, providing this organism with a bet-hedging solution to survival in fluctuating environments.


Establishment of infection by spleen necrosis virus: inhibition in stationary cells and the role of secondary infection.
The relationship of two early events in the establishment of infection by avian retroviruses, the inhibition of viral DNA synthesis in stationary avian cells and the secondary infection which occurs after infection of replicating cells, was investigated. When neutralizing antibody to spleen necrosis virus was used to prevent secondary infection, the amount of unintegrated linear spleen necrosis virus DNA detected was much lower in infected stationary cells than in infected replicating cells. The amount of unintegrated linear spleen necrosis virus DNA in stationary cells was less than one copy per cell even at high multiplicities of infection. Viral DNA synthesis resumed after stimulation of the cells to replicate. The time of this viral DNA synthesis was closely correlated with renewed cellular DNA synthesis. In addition, blocking secondary infection of replicating cells prevented the rate of virus production from reaching the high levels usually associated with a normal productive infection by SNV. Virus production increased if secondary infection was allowed. However, this rise in virus production was not proportional to the amounts of viral DNA integrated after secondary infection.


A high-density cytogenetic map of the Aegilops tauschii genome incorporating retrotransposons and defense-related genes: insights into cereal chromosome structure and function.
Aegilops tauschii (Coss.) Schmal. (2n = 2x = 14, DD) (syn. A. squarrosa L.; Triticum tauschii) is well known as the D-genome donor of bread wheat (T. aestivum, 2n = 6x = 42, AABBDD). Because of conserved synteny, a high-density map of the A. tauschii genome will be useful for breeding and genetics within the tribe Triticeae which besides bread wheat also includes barley and rye. We have placed 249 new loci onto a high-density integrated cytological and genetic map of A. tauschii for a total of 732 loci making it one of the most extensive maps produced to date for the Triticeae species. Of the mapped loci, 160 are defense-related genes. The retrotransposon marker system recently developed for cultivated barley (Hordeum vulgare L.) was successfully applied to A. tauschii with the placement of 80 retrotransposon loci onto the map. A total of 50 microsatellite and ISSR loci were also added. Most of the retrotransposon loci, resistance (R), and defense-response (DR) genes are organized into clusters: retrotransposon clusters in the pericentromeric regions, R and DR gene clusters in distal/telomeric regions. Markers are non-randomly distributed with low density in the pericentromeric regions and marker clusters in the distal regions. A significant correlation between the physical density of markers (number of markers mapped to the chromosome segment/physical length of the same segment in microm) and recombination rate (genetic length of a chromosome segment/physical length of the same segment in microm) was demonstrated. Discrete regions of negative or positive interference (an excess or deficiency of crossovers in adjacent intervals relative to the expected rates on the assumption of no interference) was observed in most of the chromosomes. Surprisingly, pericentromeric regions showed negative interference. Islands with negative, positive and/or no interference were present in interstitial and distal regions. Most of the positive interference was restricted to the long arms. The model of chromosome structure and function in cereals with large genomes that emerges from these studies is discussed.


Do older adults show less confidence in their monitoring of learning?
Although aging has a minimal effect on the accuracy of people's judgments of learning (JOLs) at predicting future memory performance, older adults may be less confident in these memory judgments--similar to the age declines often reported with memory self-efficacy. To evaluate this possibility, the authors had younger and older adults make JOLs for paired associates and rate their confidence in the accuracy of each JOL. Age-related declines in confidence in judgments were evident for immediate JOLs but not for delayed JOLs. Implications of these outcomes for theory of JOLs and explaining age-related differences in self-regulated study are discussed.


Proteolytically activated anti-bacterial hydrogel microspheres.
Hydrogels are finding increased clinical utility as advances continue to exploit their favorable material properties. Hydrogels can be adapted for many applications, including surface coatings and drug delivery. Anti-infectious surfaces and delivery systems that actively destroy invading organisms are alternative ways to exploit the favorable material properties offered by hydrogels. Sterilization techniques are commonly employed to ensure the materials are non-infectious upon placement, but sterilization is not absolute and infections are still expected. Natural, anti-bacterial proteins have been discovered which have the potential to act as anti-infectious agents; however, the proteins are toxic and need localized release to have therapeutic efficacy without toxicity. In these studies, we explore the use of the glutathione s-transferase (GST) to anchor the bactericidal peptide, melittin, to the surface of poly(ethylene glycol) diacrylate (PEGDA) hydrogel microspheres. We show that therapeutic levels of protein can be anchored to the surface of the microspheres using the GST anchor. We compared the therapeutic efficacy of recombinant melittin released from PEGDA microspheres to melittin. We found that, when released by an activating enzyme, thrombin, recombinant melittin efficiently inhibits growth of the pathogenic bacterium Streptococcus pyogenes as effectively as melittin created by solid phase peptide synthesis. We conclude that a GST protein anchor can be used to immobilize functional protein to PEGDA microspheres and the protein will remain immobilized under physiological conditions until the protein is enzymatically released.


COVID-19 vaccination effectiveness in the population of Friuli Venezia Giulia, North-East Italy. Control of bias associated with divergent compliance to policies in a test-negative case-control study.
Vaccine effectiveness (VE) studies consolidate knowledge of real-world effectiveness in different contexts. However, methodological issues may undermine their conclusions: to assess the VE against COVID-19 within the Italian population, a specific threat to validity is related to the consequences of divergent compliance to the Green Pass policy. To address this challenge we conducted a test negative case-control (TNCC) study and multiple sensitivity analysis among residents aged ≥ 12 in Friuli Venezia Giulia Region (FVG), North-east Italy, from February 1, 2021 to March 31, 2022. Information regarding 211,437 cases of COVID-19 infection and 845,748 matched controls was obtained from the regional computerized health database. The investigation considered: COVID-19 infection, hospitalization, and death. Multiple conditional logistic regressions adjusted for covariates were performed and VE was estimated as (1-OR COVID-19vaccinated vs. unvaccinated)x100. Mediation analyses were carried out to offset potential collider variables, particularly, the number of swabs performed after the introduction of pandemic restrictions. Full-cycle VE against infection decreased from 96% (95% CI: 96, 97) in the Alpha period to 43% (95% CI: 42, 45) in the Omicron period. Booster dose raised the protection in Omicron period to 67% (95% CI: 66, 67). Against the evasive Omicron variant, the protection of the booster dose was 87% (95% CI: 83, 90) for hospitalization and 90% (95% CI: 82, 95) for death. The number of swabs performed was included as a covariate in the adjustments, and the mediation analysis confirmed that it was a strong mediator between vaccination and COVID-19-related outcomes. The study suggests that, under similar TNCC settings, mediation analysis and adjustment for number of diagnostic tests should be included, as an effective approach to the challenge of differential testing behavior that may determine substantial selection bias. This correction allowed us to align with results from other studies that show how full-cycle VE against infection was initially high but decreased over time by variant circulation, counterbalanced by booster dose that raised protection across variants and outcome severity.


Semiholographic quantum criticality.
We identify the near-critical effective theory (EFT) for a wide class of low-temperature phase transitions found via holography. The EFT is of the semiholographic type and describes both holographic Berezinskii-Kosterlitz-Thouless and second-order transitions with nontrivial scaling. It is a simple generalization of the Ginzburg-Landau-Wilson paradigm to systems with an emergent (or hidden) conformal sector. Having identified the near-critical EFT, we explore its basic phenomenology by computing critical exponents and low-frequency correlators.


Effect of the rearing system on financial returns from Murciano-Granadina breed goats.
In dairy goats, the kid rearing system can have critical importance in financial returns. Commonly used criteria for the choice of rearing system are not always clear due to the high number of factors involved. The aim of this study was to quantify all those factors to facilitate decision making. So, the effect of two different kid rearing systems, mixed rearing system (MRS) and artificial rearing system (ARS), on milk yield, milk composition and somatic cell count (SCC), milk yield loss at weaning for MRS, kid growth and costs of the different traits on the financial returns in Murciano-Granadina breed goats was studied. Twenty-four goats per group were used. In the MRS, goats reared only one kid, which had free access to goat milk 24 h a day and were weaned at week 6 of lactation, whereas kids in the ARS were separated from their mothers at kidding, colostrum and artificially reared. In both systems, dams were machine-milked once a day throughout lactation and the records took place weekly. Potential milk yield was estimated according to the oxytocin method up to week 12 of lactation, and was similar for both rearing systems, although a 12.3% drop in potential milk yield at weaning was observed for MRS. During the first 6 weeks of lactation, marketable milk was lower for dams in MRS compared to those in ARS (72.1 v. 113.0 l), but similar for the rest of the experiment (101.5 v. 99.4 l, respectively). Marketable milk composition and SCC throughout the 12 weeks of lactation were unaffected by the rearing system. Artificial rearing system entailed an increment in production cost of 22.2€ per kid compared to the rearing by MRS. A similar economic return per goat and kid was obtained from ARS and MRS in this experiment, although, due to one herd's prolificacy of 1.8, the actual results would be 16.2€ per goat in favour of MRS. The real interest of this experiment may be the possibility of extrapolation to different flocks with diverse levels of milk production, prolificacy and prices and costs for incomes and outputs, to estimate the production system that increases returns. In conclusion, the results showed an increase in the cost of €22.2 per kid bred in the ARS, compared to the MRS, and a final return of 16.2€ per goat in favour of the mixed system.


Endometrial cancer. Prevention, detection, management, and follow up.
To review risk factors for uterine cancer; to discuss strategies for detecting uterine cancer; to outline prognostic factors and treatment; and to review the role of follow up for patients who have completed primary therapy. MEDLINE was searched from January 1996 to June 1998 using the terms endometrial neoplasms, estrogen replacement therapy, hormone replacement therapy, tamoxifen, and screening. Only English language articles were reviewed. Study types included reviews. Bibliographies of articles found were searched for further relevant titles. Causation literature is available from well conducted cohort trials. Treatment recommendations are based in part on prognostic information and a few randomized controlled trials. Risk factors, both intrinsic and extrinsic, are associated with uterine cancer. Family physicians have a role in preventing disease by ensuring that all women with uteri in situ using hormone replacement therapy (HRT) have progesterone therapy as part of the HRT regimen. Detection is crucial; abnormal uterine bleeding or undiagnosed postmenopausal bleeding warrants investigation with endometrial biopsy. The goal of surgery is to remove the uterus and ovaries and identify factors that make the disease at high risk of recurrence. Although adjuvant radiation therapy does not prolong survival, it does alter the pattern of disease recurrence. The goal of follow up after primary therapy is to identify recurrent disease while it is still curable. Family physicians play an important role in preventing uterine cancer, initiating early diagnosis of disease, and in the future, might be more actively involved in caring for patients following primary therapy.


Complete endovascular occlusion of a cranial dural fistula using a venous "to the point" approach.
Cranial dural arteriovenous fistulas are commonly treated using an endovascular method. In comparison to intracerebral arteriovenous malformations, it is important to reach the venous part of these malformations to maintain a complete occlusion. Therefore, often the venous side is totally occluded using coils and∕or glue. We describe a patient with an initially Type IIab (Cognard classification) left occipital cranial fistula. The patient suffered from an intense pulsate tinnitus. Therefore, the first embolization was performed using an approach via the dilated left middle meningeal artery using Onyx. The shunt of the fistula was reduced significantly but total occlusion was impossible. Therefore, the venous approach was used. Over a guiding catheter in the sigmoid sinus, the venous side of the fistula could be reached with a microcatheter. This part of the fistula was then completely occluded using coated and bare coils, without occluding the adjacent sinus. Control angiography of all previous feeders showed a complete occlusion of the fistula (used classification: Cognard). The fistula was entirely occluded. The patient's outcome was excellent. The patient did not develop any symptoms and no complication occurred due to the treatment. Direct occlusion of the venous part of an arteriovenous cranial fistula can be an option before an occlusion of the sinus has to be performed. This approach can lead to reduction of risk during the endovascular procedure and risk reduction in long-term follow-up.


Why blind diabetics with renal failure should be offered treatment.
During May 1978 to April 1983 this renal dialysis unit treated 65 patients by continuous ambulatory peritoneal dialysis. Of these, 24 had type I (insulin dependent) diabetes, of whom 20 were blind; eight had type II (non-insulin dependent) diabetes, of whom three were blind; and 33 did not have diabetes and were not blind. The cumulative actuarial survival rates of these patients at five years were 60% for blind diabetics, 40% for sighted diabetics, and 46% for the non-diabetics. Of the 23 blind patients, 22 successfully achieved self care, including the self administration of insulin into the peritoneal dialysis solution. Blind patients had the least peritonitis and fewest complications of continuous ambulatory peritoneal dialysis, and none objected to the treatment or requested to be taken off it or be allowed to die. It was concluded that blind diabetic patients with renal failure showed both the will and the ability to stay alive and that their treatment was worth while.


Ovarian blood vessel occlusion as a surgical sterilization method in rats.
To evaluate the female sterilization by occlusion of the ovarian blood flow, using the rat as experimental model. Fifty-five females rats were divided into four groups: I (n=10), bilateral ovariectomy, euthanized at 60 or 90 days; II (n=5), opening the abdominal cavity, euthanized at 90 days; III (n=20), bilateral occlusion of the ovarian blood supply using titanium clips, euthanized at 60 or 90 days; and IV (n=20), bilateral occlusion of the ovarian blood supply using nylon thread, euthanized at 60 or 90 days. The estrous cycle was monitored by vaginal cytology. After euthanasia, the reproductive tissues were evaluated histologically. Ovarian atresia was identified macroscopically at 60 days after surgery in the rats in groups III and IV; however, most of the rats in group III maintained cyclicity. Histology of the tissues from group IV revealed that the ovarian tissue was replaced by dense fibrous connective tissue that was slightly vascularized and that intact follicles were absent by 90 days. Ovarian blood vessels occluded caused ischemia, leading to progressive tissue necrosis, and bilateral occlusion using a nylon ligature is a viable method for surgical sterilization.


Vesicostomy and Colostomy in a Premature Neonate With Posterior Urethral Valves, Bilateral Dysplastic Kidneys, and High Imperforate Anus: The Challenge of Stoma Placement.
Although anorectal malformations are often associated with urinary tract abnormalities, the association with posterior urethral valves is exceptionally rare. We report a unique case of a premature (35 gestational weeks) male neonate born with posterior urethral valves, bilateral dysplastic kidneys, and imperforate anus, successfully treated by Blocksom vesicostomy and left upper quadrant loop colostomy. The challenges involving placement of both stomas in a small abdominal wall of a 2200 g premature neonate are discussed.


Chemical studies on antioxidant mechanisms and free radical scavenging properties of lignans.
The antioxidant activity, in terms of radical scavenging capacity, of altogether 15 different lignans was measured by monitoring the scavenging of the free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH). The effect of differences in skeletal arrangement or the degree of oxidation of the lignans was investigated in a structure-activity relationship study. A large variety in the radical scavenging capacities of the different lignans was observed and related to some structural features. Lignans with catechol (3,4-dihydroxyphenyl) moieties exhibited the highest radical scavenging capacity, while the corresponding guaiacyl (3-methoxy-4-hydroxyphenyl) lignans showed a slightly weaker scavenging capacity. In addition, the butanediol structure was found to enhance the activity, whereas a higher degree of oxidation at the benzylic positions decreased the activity. Additionally, the readily available lignans (-)-secoisolariciresinol, a mixture of hydroxymatairesinol epimers and (-)-matairesinol were studied in more detail, including kinetic measurements and identification of oxidation products in the reactions with DPPH and ABAP (2,2-azobis(2-methylpropionamidine) dihydrochloride. The identification of reaction products, by GC-MS, HPLC-MS and NMR spectroscopy, showed that dimerisation of the two aromatic moieties was the major radical termination reaction. Also, the formation of adducts was a predominant reaction in the experiments with ABAP. The kinetic data obtained from the reactions between the lignans and DPPH indicated a complex reaction mechanism.


NewB for newbies: a randomized control trial training housestaff to perform neonatal intubation with direct and videolaryngoscopy.
Competency rates in neonatal intubation among pediatric residents are low and currently not meeting ACGME/AAP standards. The aim of this study was to compare standard bedside teaching of neonatal endotracheal intubation to a computer module, as well as introduce residents to the emerging technology of videolaryngoscopy. The study population consisted of The University of Texas Health Science Center at San Antonio Pediatric interns/residents and PGY-1 Anesthesia interns rotating through the NICU. Prior to participating in the study, the residents completed a survey addressing past experiences with intubation, comfort level, and prior use of direct and videolaryngoscopy. Participants then performed timed trials of both direct and videolaryngoscopy on the SimNewB(®). They had up to three attempts to successfully intubate, with up to 30 s on each attempt. After randomization, participants received one of the following teaching interventions: standard, computer module, or both. This was followed by a second intubation trial and survey completion. Thirty residents were enrolled in the study. There was significant improvement in time to successful intubation in both methods after any teaching intervention (direct 22.0 ± 13.4 s vs 14.7 ± 5.9 s, P = 0.002 and videolaryngoscopy 42.2 ± 29.3 s vs 26.8 ± 18.6 s, P = 0.003). No differences were found between the types of teaching. Residents were faster at intubating with direct laryngoscopy compared to videolaryngoscopy before and after teaching. By the end of the study, only 33% of residents preferred using videolaryngoscopy over direct laryngoscopy, but 76% felt videolaryngoscopy was better to teach intubation. Both standard teaching and computer module teaching of neonatal intubation on a mannequin model results in improved time to successful intubation and overall improved resident confidence with intubation equipment and technique. Although intubation times were lower with direct laryngoscopy compared to videolaryngoscopy, the participating residents felt that videolaryngoscopy is an important educational tool.


Discovery of high-confidence human protein-coding genes and exons by whole-genome PhyloCSF helps elucidate 118 GWAS loci.
The most widely appreciated role of DNA is to encode protein, yet the exact portion of the human genome that is translated remains to be ascertained. We previously developed PhyloCSF, a widely used tool to identify evolutionary signatures of protein-coding regions using multispecies genome alignments. Here, we present the first whole-genome PhyloCSF prediction tracks for human, mouse, chicken, fly, worm, and mosquito. We develop a workflow that uses machine learning to predict novel conserved protein-coding regions and efficiently guide their manual curation. We analyze more than 1000 high-scoring human PhyloCSF regions and confidently add 144 conserved protein-coding genes to the GENCODE gene set, as well as additional coding regions within 236 previously annotated protein-coding genes, and 169 pseudogenes, most of them disabled after primates diverged. The majority of these represent new discoveries, including 70 previously undetected protein-coding genes. The novel coding genes are additionally supported by single-nucleotide variant evidence indicative of continued purifying selection in the human lineage, coding-exon splicing evidence from new GENCODE transcripts using next-generation transcriptomic data sets, and mass spectrometry evidence of translation for several new genes. Our discoveries required simultaneous comparative annotation of other vertebrate genomes, which we show is essential to remove spurious ORFs and to distinguish coding from pseudogene regions. Our new coding regions help elucidate disease-associated regions by revealing that 118 GWAS variants previously thought to be noncoding are in fact protein altering. Altogether, our PhyloCSF data sets and algorithms will help researchers seeking to interpret these genomes, while our new annotations present exciting loci for further experimental characterization.


A New Light-Emitting, Fabric-Based Device for Photodynamic Therapy of Actinic Keratosis: Protocol for a Randomized, Controlled, Multicenter, Intra-Individual, Phase II Noninferiority Study (the Phosistos Study).
Actinic keratosis (AK) is a common early in situ skin carcinoma caused by long-term sun exposure and usually develops on sun-exposed skin areas. Left untreated, AK may progress to squamous cell carcinoma. To prevent such risk, most clinicians routinely treat AK. Therapy options for AK include cryotherapy, topical treatments, curettage, excision surgery, and photodynamic therapy (PDT). The aim of this study is to assess the noninferiority, in terms of efficacy at 3 months, of a PDT protocol involving a new light-emitting device (PDT using the Phosistos protocol [P-PDT]) compared with the conventional protocol (PDT using the conventional protocol [C-PDT]) in the treatment of AK. In this randomized, controlled, multicenter, intra-individual, phase II noninferiority clinical study, subjects with AK of the forehead and scalp are treated with P-PDT on one area and with C-PDT on the contralateral area. In both areas, lesions are prepared and methyl aminolevulinate (MAL) is applied. Thirty minutes after MAL application, the P-PDT area is exposed to red light at low irradiance (1.3 mW/cm2) for 2.5 hours so that a light dose of 12 J/cm2 is achieved. In the control area (C-PDT area), a 37 J/cm2 red light irradiation is performed 3 hours after MAL application. Recurrent AK at 3 months is retreated. The primary end point is the lesion complete response rate at 3 months. Secondary end points include pain scores at 1 day, local tolerance at 7 days, lesion complete response rate at 6 months, cosmetic outcome at 3 and 6 months, and patient-reported quality of life and satisfaction throughout the study. A total of 45 patients needs to be recruited. Clinical investigations are complete: 46 patients were treated with P-PDT on one area (n=285 AK) and with C-PDT on the contralateral area (n=285 AK). Data analysis is ongoing, and statistical results will be available in the first half of 2019. In case of noninferiority in efficacy and superiority in tolerability of P-PDT compared with C-PDT, P-PDT could become the treatment of choice for AK. ClinicalTrials.gov NCT03076892; https://clinicaltrials.gov/ct2/show/NCT03076892 (Archived by WebCite at http://www.webcitation.org/779qqVKek). DERR1-10.2196/12990.


Prognostic relevance of lymphocytopenia, monocytopenia and lymphocyte-to-monocyte ratio in primary myelodysplastic syndromes: a single center experience in 889 patients.
Current prognostic models for myelodysplastic syndromes (MDS), including the Revised International Prognostic Scoring System (IPSS-R), do not account for host immunity. We retrospectively examined the prognostic relevance of monocytopenia, lymphocytopenia and lymphocyte-to-monocyte ratio (LMR) in a cohort of 889 patients with primary MDS. After a median follow-up of 27 months, 712 (80%) deaths and 116 (13%) leukemic transformation were documented. In univariate analysis, subnormal absolute lymphocyte count (ALC) <0.9 × 109/l; P=0.001), ALC<1.2 × 109/l (P=0.0002), subnormal absolute monocyte count (AMC) <0.3 × 109/l (P=0.0003), LMR (P⩽0.0001) and LMR⩾5 (P=0.03) were all associated with inferior overall survival. In multivariable analysis that included other risk factors, significance was retained for LMR (P=0.02) and became borderline for ALC <1.2 × 109/l (P=0.06). Analysis in the context of IPSS-R resulted in P-values of 0.06 for ALC<1.2 × 109/l, 0.7 for monocytopenia and 0.2 for LMR. Leukemia-free survival was not affected by ALC, AMC or LMR. The observations from the current study suggest a possible detrimental role for altered host immunity in primary MDS, which might partly explain the therapeutic benefit of immune-directed therapy, including the use of immune modulators; however, IPSS-R-independent prognostic value for either ALC or AMC was limited.


Single-cell atlas of the aging mouse colon.
We performed massive single-cell sequencing in the aging mouse colonic epithelium and immune cells. We identified novel compartment-specific markers as well as dramatic aging-associated changes in cell composition and signaling pathways, including a shift from absorptive to secretory epithelial cells, depletion of naive lymphocytes, and induction of eIF2 signaling. Colon cancer is one of the leading causes of death within the western world, incidence of which increases with age. The colonic epithelium is a rapidly renewing tissue, tasked with water and nutrient absorption, as well as hosting intestinal microbes. The colonic submucosa is populated with immune cells interacting with and regulating the epithelial cells. However, it is unknown whether compartment-specific changes occur during aging and what impact this would cause. We show that both epithelial and immune cells differ significantly between colonic compartments and experience significant age-related changes in mice. We found a shift in the absorptive-secretory cell balance, possibly linked to age-associated intestinal disturbances, such as malabsorption. We demonstrate marked changes in aging immune cells: population shifts and interactions with epithelial cells, linking cytokines (Ifn-γ, Il1B) with the aging of colonic epithelium. Our results provide new insights into the normal and age-associated states of the colon.


Pulmonary blastoma: a report of two cases and a review of the literature.
Pulmonary blastoma is the rarest malignant tumour of the lung. Two more cases are reported and the literature is reviewed. The first case, a woman, is the longest recorded survivor. An examination of all the reported cases shows that the tumour is less common and less agressive in women.


A consensus in Korea regarding a protocol to reduce preanalytical sources of variability in the measurement of the cerebrospinal fluid biomarkers of Alzheimer's disease.
Cerebrospinal fluid (CSF) can provide vital informative about pathological processes occurring in the brain. In particular, the CSF concentrations of Aβ42, tTau, and pTau181 are useful for the early diagnosis of Alzheimer's disease (AD). However, many studies have demonstrated that confounding factors related to the preanalytical processing of CSF can seriously influence measurements of these AD biomarkers. It is therefore important to develop a standardized protocol for the acquisition and handling of CSF, particularly with regard to the types of tube used for collection and storage, the proper aliquot volume, blood contamination, and the number of tube transfers and freeze-thaw cycles, because these aspects of the procedure have been shown to affect AD biomarker measurements. A survey of the impact of several individual preanalytical procedures on the measurement of AD biomarkers in CSF was conducted for this review article, and the implications of the differences among them are discussed. Furthermore, following a review of the procedures used in Korean and international biomarker laboratories, a consensus was reached among a cooperative Korean multicenter research group regarding a standardized protocol for the analysis of AD biomarkers in CSF. All efforts were made to be stringent regarding the controversial issues associated with this protocol, thus minimizing the confounding influence of various factors on current investigations using established AD biomarkers and on future studies using novel biomarkers of AD and other neurodegenerative disorders.


Promoting clinical reasoning in general practice trainees: role of the clinical teacher.
Clinical reasoning requires knowledge, cognition and metacognition, and is contextually bound. Clinical teachers can and should play a key role in explicitly promoting clinical reasoning. The aim of this article is to relate the clinical reasoning literature to the general practice or family medicine context, and to provide clinical teachers with strategies to promote clinical reasoning. It is important that the clinical teacher teaches trainees the specific skills sets of the expert general practitioner (e.g. synthesising skills, recognising prototypes, focusing on cues and clues, using community resources and dealing with uncertainty) in order to promote clinical reasoning in the context of general practice or family medicine. Clinical teachers need to understand their own reasoning processes as well as be able to convey that knowledge to their trainees. They also need to understand the developmental stages of clinical reasoning and be able to nurture each trainee's own expertise. Strategies for facilitating effective clinical reasoning in trainees include adequate exposure to patients, offering the trainees opportunity for reflection and feedback, and coaching on the techniques of reasoning in the general practice context. The journey to expertise in clinical reasoning is unique to each clinician, with different skills developing at different rates, depending on content, context and past experience. Doctors enter into general practice training with the building blocks of biomedical and clinical knowledge and a desire to learn how to be a general practitioner. Clinical teachers are integral in the process of helping trainees learn how to 'think like a general practitioner'.


Automatic nystagmus detection and quantification in long-term continuous eye-movement data.
Symptoms of dizziness or imbalance are frequently reported by people over 65. Dizziness is usually episodic and can have many causes, making diagnosis problematic. When it is due to inner-ear malfunctions, it is usually accompanied by abnormal eye-movements called nystagmus. The CAVA (Continuous Ambulatory Vestibular Assessment) device has been developed to provide continuous monitoring of eye-movements to gain insight into the physiological parameters present during a dizziness attack. In this paper, we describe novel algorithms for detecting short periods of artificially induced nystagmus from the long-term eye movement data collected by the CAVA device. In a blinded trial involving 17 healthy subjects, each participant induced nystagmus artificially on up to eight occasions by watching a short video on a VR headset. Our algorithms detected these short periods with an accuracy of 98.77%. Additionally, data relating to vestibular induced nystagmus was collected, analysed and then compared to a conventional technique for assessing nystagmus during caloric testing. The results show that a range of nystagmus can be identified and quantified using computational methods applied to long-term eye-movement data captured by the CAVA device.


Collateral mesenteric circulation.
The origins of historical terms, such as "Arc of Riolan" and "marginal artery of Drummond" are traced herein with emphasis on the inherent confusion caused when these terms are used. Basic mesenteric anatomy is briefly mentioned and pathologic anatomy with its altered direction of blood flow induced by atherosclerosis is stressed. The significance of the meandering mesenteric artery as the main collateral vessel between the superior and inferior mesenteric artery is emphasized along with preoperative and intraoperative ways to ascertain whether or not the origin of this latter vessel can be safely ligated. Specific operations, such as abdominal aortic aneurysmorrhaphy and sigmoid colectomy, which can potentially interfere with blood flow in the meandering mesenteric artery, are discussed in an attempt to prevent postoperative necrosis of any portion of the intestine that may have deficient mesenteric blood flow.


Relationship of gender and age on thyroid hormone parameters in a large Chinese population.
Objective This study aimed to present the impact of age and gender on thyroid hormone levels in a large Chinese population with sufficient iodine intake. Subjects and methods A total of 83643 individuals were included and were stratified by age and gender. The median, 2.5th and 97.5th of thyrotropin (TSH), free triiodothyronine (FT3), free thyroxine (FT4) and FT3/FT4 ratio were calculated for both genders for every decade from 18 to over 80 years. TSH, FT3, FT4, FT3/FT4 distribution in each age group was evaluated for females and males using smoothing splines in the generalized additive models (GAM). TSH concentrations were compared in the different age groups in gender. Results In the over 80s age group, the TSH level (median: 2.57 mIU/L, 2.5th-97.5th: 0.86-7.56 mIU/L) was significantly higher than other age groups, irrespective to gender (P<0.001). Females had a higher TSH value than males in all age groups (P<0.001). Results of the smoothing curves showed that TSH increased with age, FT3 concentration was higher in males than in females and the tendency of the FT3/FT4 ratio was basically similar to that of FT3. TSH concentration in the 50s age group (median 2.48 mIU/L for females versus 2.00 mIU/L for males) was significantly higher than that in the 30s age group (median 2.18 mIU/L for females versus median 1.85 mIU/L for males). Conclusions In accord with increasing TSH values during aging, females and older adults have lower FT3 values and lower FT3/FT4 ratios, while the FT4 values remain stable.


Use of tissue meshing technique to facilitate side to side closure of large defects.
Primary closure of a large wound usually needs flaps of sophisticated design or skin grafts, both require more skill and wound care. Motley and Holt first reported the use of meshed advancement flap, a relative simple technique to close large defects of the lower leg in five patients. To report the use of tissue meshing technique to close large wounds with significant tension on various sites of the body. Six patients with large benign or malignant neoplasms at various sites of the body were included. Tissue meshing technique was used to facilitate wound closure after elliptical excision of the tumors at office visits. The wound defects, ranging from 3.0-3.5 cm in width, were closed with satisfactory cosmetic results, except for the occurrence of transient small hypertrophic scars in one patient. There was no complication of wound dehiscence, ischemia, infection or hematoma. Tissue meshing technique is a simple procedure and appears to be a satisfactory alternative to facilitate the closure of large wounds under tension. This technique is suitable for most body sites excluding central face and neck because there may be a stippled appearance in the area of meshing.


Quantitative agent based model of user behavior in an Internet discussion forum.
The paper presents an agent based simulation of opinion evolution, based on a nonlinear emotion/information/opinion (E/I/O) individual dynamics, to an actual Internet discussion forum. The goal is to reproduce the results of two-year long observations and analyses of the user communication behavior and of the expressed opinions and emotions, via simulations using an agent based model. The model allowed to derive various characteristics of the forum, including the distribution of user activity and popularity (outdegree and indegree), the distribution of length of dialogs between the participants, their political sympathies and the emotional content and purpose of the comments. The parameters used in the model have intuitive meanings, and can be translated into psychological observables.


Separation of ornithine and lysine activities of the ornithine-transcarbamylase-catalyzed reaction.
Several lines of evidence are presented that an entity is present in mitochondria which converts lysine and carbamylphosphate to homocitrulline, distinct from the ornithine transcarbamylase (OTC): lack of inhibition by lysine of OTC with ornithine as substrate at the pH of the mitochondrial matrix, a Km for lysine of 6.3 mmol/l in the crude mitochondrial extract, versus a Km of 55.3 mmol/l after partial purification of OTC, decrease of the specific activity of OTC with lysine as substrate and increase of the specific activity with ornithine as substrate after heat denaturation, and separation of the activities for ornithine and lysine after isoelectric focusing. This would explain the excretion of homocritrulline in the HHH-syndrome, saccharopinuria, citrullinemia and hyperlysinemia. The fact that homocitrulline excretion is not observed in OTC deficiency suggests that the activity responsible for homocitrulline excretion is closely related to OTC.


Effects of invasive fish and quality of water and sediment on macrophytes biomass, and their consequences for the waterbird community of a Mediterranean floodplain.
Floodplains are among the most threatened ecosystems world-wide because of multiple stressors, i.e., invasive species, pollution and aquifer overexploitation; the Tablas de Daimiel National Park (Spain) is a clear example of these kinds of impact. This work aims to test whether invasive fish and/or the water and sediment quality are significant drivers of the decline of stonewort (Chara spp.) meadows in the Tablas de Daimiel, investigating how this could explain changes observed in the waterbird community. Bird surveys performed monthly between June 2010 and April 2014 have shown that herbivorous species like the red-crested pochard (Netta rufina) reached historical records between September 2010 and June 2011, but have decreased since then. Piscivorous waterbirds like the great cormorant (Phalacrocorax carbo) and herons increased in population after 2011, however. These changes may be due to the decline of Chara spp. meadows, connected to overexploitation by herbivores, or to changes in water and sediment quality. To test this hypothesis, we studied the growth of Chara spp. biomass in ten sites of the Tablas de Daimiel, where experimental exclosures were set up to exclude herbivory by birds, and bioturbation and herbivory by fish. Our results have shown that the absence of Chara spp. in the Tablas de Daimiel is mostly explained by presence of invasive fish (i.e. common carp). Moreover, the physicochemical characteristics of the water (lower values of conductivity and higher values of inorganic carbon and organic nitrogen), as well as of the sediment (lower values of inorganic and organic phosphorus), favour the increase of Chara spp., in the absence of the fish effect. These results led the National Park managers to begin the control of invasive fish as an urgent measure to assure the ecological conservation of this Mediterranean wetland.


Neurodevelopmental therapy and upper-extremity inhibitive casting for children with cerebral palsy.
The purpose of this research was to study the effect of intensive neurodevelopmental therapy (NDT) and upper-extremity inhibitive casting, separately or in combination, on hand function, quality of upper-extremity movement and range of motion of 73 children with spastic cerebral palsy aged 18 months to eight years. There was no significant difference between intensive or regular therapy and casting or no casting for hand function, between intensive and regular NDT, or between intensive NDT plus casting and the other groups for quality of movement and range of motion. Casting led to increased quality of movement and wrist extension after six months. Casting with NDT improved the quality of upper-extremity movement and range of motion. There appear to be no immediate benefits from intensive therapy alone.


Ambulatory cardiac surgery.
In order to move toward a program of reliable and routine ambulatory cardiac surgery there must be a paradigm change in the attitude of both patients and caregivers. The status quo must be abandoned and replaced by the pioneering attitude of the early practitioners who formed our specialty.


Superplasticity of Ti-6Al-4V Titanium Alloy: Microstructure Evolution and Constitutive Modelling.
Determining a desirable strain rate-temperature range for superplasticity and elongation-to-failure are critical concerns during the prediction of superplastic forming processes in α + β titanium-based alloys. This paper studies the superplastic deformation behaviour and related microstructural evolution of conventionally processed sheets of Ti-6Al-4V alloy in a strain rate range of 10-5-10-2 s-1 and a temperature range of 750-900 °C. Thermo-Calc calculation and microstructural analysis of the as-annealed samples were done in order to determine the α/β ratio and the grain size of the phases prior to the superplastic deformation. The strain rate ranges, which corresponds to the superplastic behaviour with strain rate sensitivity index m ˃ 0.3, are identified by step-by-step decreasing strain rate tests for various temperatures. Results of the uniaxial isothermal tensile tests at a constant strain rate range of 3 × 10-4-3 × 10-3 s-1 and a temperature range of 800-900 °C are presented and discussed. The experimental stress-strain data are utilized to construct constitutive models, with the purpose of predicting the flow stress behaviour of this alloy. The cross-validation approach is used to examine the predictability of the constructed models. The models exhibit excellent approximation and predictability of the flow behaviour of the studied alloy. Strain-induced changes in the grain structure are investigated by scanning electron microscopy and electron backscattered diffraction. Particular attention is paid to the comparison between the deformation behaviour and the microstructural evolution at 825 °C and 875 °C. Maximum elongation-to-failure of 635% and low residual cavitation were observed after a strain of 1.8 at 1 × 10-3 s-1 and 825 °C. This temperature provides 23 ± 4% β phase and a highly stable grain structure of both phases. The optimum deformation temperature obtained for the studied alloy is 825 °C, which is considered a comparatively low deformation temperature for the studied Ti-6Al-4V alloy.


Phase I/II study of albumin-bound nab-paclitaxel plus gemcitabine administered to Chinese patients with advanced pancreatic cancer.
The primary objective of this study was to evaluate the dose-limiting toxicities (DLTs) and identify the maximum-tolerated dose (MTD) and recommended dose of nab-paclitaxel plus gemcitabine as a first-line treatment in Chinese patients with advanced pancreatic ductal adenocarcinoma (PDA). Patients with previously untreated advanced PDA were treated with nab-paclitaxel followed by gemcitabine (1,000 mg/m(2)) administered intravenously for 30 min on days 1 and 8 and repeated every 21 days. Patients received nab-paclitaxel at the following dose levels: 80 mg/m(2) (n = 3), 100 mg/m(2) (n = 6), and 120 mg/m(2) (n = 12). The DLTs evaluated were elevated alanine aminotransferase and febrile neutropenia. However, there had no two out of three to six patients experienced DLTs, the MTD was not met. A total of 93 cycles were administered. The most common grade 3/4 toxicities were neutropenia (9.52 %), thrombocytopenia (4.76 %), and sensory neuropathy (4.76 %). For 12 patients receiving 120 mg/m(2), the overall response rate and disease control rate were 41.67 and 83.33 %, respectively, and the median progression-free survival and overall survival were 5.23 and 12.17 months, respectively. Treatment with albumin-bound nab-paclitaxel (120 mg/m(2)) plus gemcitabine has a favorable safety profile with an encouraging antitumor effect in Chinese patients.


Differential synthesis of 1-acyl-2-acetyl-sn-glycero-3-phosphocholine and platelet-activating factor by human inflammatory cells.
The synthesis of platelet-activating factor (PAF) and of the 1-acyl analogue of PAF, 1-acyl-2-acetyl-sn-glycero-3-phosphocholine (1-acyl-2-acetyl-GPC) was examined in seven human cell preparations (lung mast cell, basophil, endothelial cell, neutrophil, eosinophil, lung macrophage, platelet) and in human lung fragments. Cells were activated by either an appropriate receptor-mediated stimulus or by ionophore A23187 in the presence of [3H]acetate. All cell types, with the exception of the platelet, responded to stimulation with at least a twofold increase in the formation of labeled 1-radyl-2-acetyl-GPC as compared with control values. A23187 was the more potent stimulus in all cell types examined except the lung mast cell, in which anti-IgE consistently induced the synthesis of more 1-radyl-2-acetyl-GPC. Human lung fragments stimulated by anti-IgE, Ag Amb a I (after passive sensitization), or A23187 also incorporated [3H]acetate into 1-radyl-2-acetyl-GPC. Subclass analysis of 1-radyl-2-acetyl-GPC produced by each cell indicated that the cell types examined can be divided into two groups according to the predominant type of 1-radyl-2-acetyl-GPC produced. Some cell types (mast cell, basophil, endothelial cell) produced predominantly 1-acyl-2-acetyl-GPC, whereas others (neutrophil, eosinophil, lung macrophage) produced almost exclusively PAF. In some cell types, such as the lung mast cell and the basophil, A23187 stimulation increased the synthesis of PAF relative to 1-acyl-2-acetyl-GPC as compared with anti-IgE stimulation. In the lung fragments, [3H]acetate was predominantly incorporated into 1-acyl-2-acetyl-GPC upon IgE-mediated stimulation (anti-IgE, Amb a I) and into PAF upon A23187 stimulation. The differential production of these two phospholipids was confirmed by determining their sensitivity to lipase A1 and phospholipase A2 hydrolysis and by HPLC. These data demonstrate that 1-acyl-2-acetyl-GPC can be synthesized by a variety of human cells involved in the inflammatory reaction. This finding raises fundamental questions about the biologic role of this molecule and the factors regulating its synthesis within inflammatory cells.


Effect of oxygen on cardiac differentiation in mouse iPS cells: role of hypoxia inducible factor-1 and Wnt/beta-catenin signaling.
Disturbances in oxygen levels have been found to impair cardiac organogenesis. It is known that stem cells and differentiating cells may respond variably to hypoxic conditions, whereby hypoxia may enhance stem cell pluripotency, while differentiation of multiple cell types can be restricted or enhanced under hypoxia. Here we examined whether HIF-1alpha modulated Wnt signaling affected differentiation of iPS cells into beating cardiomyocytes. We investigated whether transient and sustained hypoxia affects differentiation of cardiomyocytes derived from murine induced pluripotent stem (iPS) cells, assessed the involvement of HIF-1alpha (hypoxia-inducible factor-1alpha) and the canonical Wnt pathway in this process. Embryoid bodies (EBs) derived from iPS cells were differentiated into cardiomyocytes and were exposed either to 24 h normoxia or transient hypoxia followed by a further 13 days of normoxic culture. At 14 days of differentiation, 59 ± 2% of normoxic EBs were beating, whilst transient hypoxia abolished beating at 14 days and EBs appeared immature. Hypoxia induced a significant increase in Brachyury and islet-1 mRNA expression, together with reduced troponin C expression. Collectively, these data suggest that transient and sustained hypoxia inhibits maturation of differentiating cardiomyocytes. Compared to normoxia, hypoxia increased HIF-1alpha, Wnt target and ligand genes in EBs, as well as accumulation of HIF-1alpha and beta-catenin in nuclear protein extracts, suggesting involvement of the Wnt/beta-catenin pathway. Hypoxia impairs cardiomyocyte differentiation and activates Wnt signaling in undifferentiated iPS cells. Taken together the study suggests that oxygenation levels play a critical role in cardiomyocyte differentiation and suggest that hypoxia may play a role in early cardiogenesis.


Big data for health.
This paper provides an overview of recent developments in big data in the context of biomedical and health informatics. It outlines the key characteristics of big data and how medical and health informatics, translational bioinformatics, sensor informatics, and imaging informatics will benefit from an integrated approach of piecing together different aspects of personalized information from a diverse range of data sources, both structured and unstructured, covering genomics, proteomics, metabolomics, as well as imaging, clinical diagnosis, and long-term continuous physiological sensing of an individual. It is expected that recent advances in big data will expand our knowledge for testing new hypotheses about disease management from diagnosis to prevention to personalized treatment. The rise of big data, however, also raises challenges in terms of privacy, security, data ownership, data stewardship, and governance. This paper discusses some of the existing activities and future opportunities related to big data for health, outlining some of the key underlying issues that need to be tackled.


Lysine and α-Aminoisobutyric Acid Conjugated Bioinspired Polydopamine Surfaces for the Enhanced Antibacterial Performance of the Foley Catheter.
Microbial adhesion onto implanted devices was reduced by the immobilization of amino acid lysine and α-aminoisobutyric acid to polydopamine functionalized PET films and Foley catheters. The polydopamine functionalized film was prepared by a dip coating method followed by incorporation of biocompatible amino acids to prepared films. The purpose of development of the modified pDA film is to improve the anti-biofouling and antibacterial activity of the film which can be successfully applied for medical devices. The characterization of modification was done using different techniques such as contact angle measurement, ATR-FTIR, FE-SEM, AFM, and XPS analysis. ATR-FTIR spectroscopy and XPS confirmed the successful amino modification of film. The anti-biofouling and antimicrobial behavior of the prepared surfaces were evaluated using the bacterial attachment and death assay. The resulting coatings repelled bacterial cell attachment and killed clinically applicable Gram-negative and Gram-positive strains. The developed coatings were applied to the Foley catheters to study the antibacterial activity by the log reduction method. The results demonstrate that tested amino acid-modified film increases the antibacterial activity of the catheters and can significantly help in reduction of nosocomial infections.


Developing a Competency Framework of Interprofessional Occupational Health Team: A First Step to Interprofessional Education in Occupational Health Field.
The present study aimed to develop a competency framework for interprofessional collaboration in an occupational health team. This study was carried out in three stages. In the first stage, the viewpoints of different stakeholders on the essential competencies of interprofessional team members in occupational health services (OHS) were assessed. In the second stage, extracted codes were converted into competencies in expert panels. After that, the extracted items were categorized by inductive content analysis approach into competency framework. In the third stage, the content validity of interprofessional competencies in OHS was evaluated. The competency framework was finalized in six competency domains including prevention, occupational disease management, occupational health assessments, inter-disciplinary and interprofessional collaboration, education, and evidence-based practice and professionalism. The framework could be developed in interprofessional education in OHS based on competency-based education approach.